Activity Measurement of 44Sc and Calibration of Activity Measurement Instruments on Production Sites and Clinics.

44Sc is a promising radionuclide for positron emission tomography (PET) in nuclear medicine. As a part of the implementation of a production site for 44Sc, precise knowledge of the activity of the product is necessary. At the Paul Scherrer Institute (PSI) and the University of Bern (UniBE), 44Sc is produced by enriched 44CaO-target irradiation with a cyclotron. The two sites use different techniques for activity measurement, namely a dose calibrator at the PSI and a gamma-ray spectrometry system at UniBE and PSI. In this work, the 44Sc was produced at the PSI, and samples of the product were prepared in dedicated containers for onsite measurements at PSI, UniBE, and the Institute of Radiation Physics (IRA) in Lausanne for precise activity measurement using primary techniques and for the calibration of the reference ionization chambers. An accuracy of 1% was obtained for the activity measurement, allowing for a precise calibration of the dose calibrator and gamma-ray spectrometry of the two production sites. Each production site now has the capability of measuring 44Sc activity with an accuracy of 2%.

Developments toward the Implementation of 44Sc Production at a Medical Cyclotron.

44Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of 44Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the 44Ca(p,n)44Sc nuclear reaction using CaO instead of CaCO3, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the 44Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce 44Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station.

[The Maintenance and Common Troubleshooting of GE MINItrace Qilin Medical Cyclotron].

This study analyzes the maintenance and common faults of GE MINItrace Qilin medical cyclotron, and studies three kinds of the machine's faults.

Pressed Solid Target Production of 89Zr and its Application for Antibody Labelling.

OBJECTIVES: Zirconium-89 ( 89Zr, t1/2=3.27d) is an important + emitting radionuclide used in Positron Emission Tomography (PET) immuno studies due to its unique characteristics and increased demand due to simple and cost-effective production capacity. Production of 89Zr is achieved primarily through solid natural yttrium targets via different target preparation methodologies, such as electrodeposition, pressed foils, and spark plasma sintering. In this study, we have investigated the pressed solid target methodology. METHODS: The Yttrium Oxide (Y2O3) powder was pressed to pellet form and stacked over a different back support plate, such as platinum (Pt), niobium (Nb), and tantalum (Ta). The target was irradiated with approximately 12 MeV proton beam for 10-60 minutes at 20µA current. The irradiated target was purified through a solid phase extraction method via hydroxamate-based resin by manual or automatic approach. The purified 89Zr was analyzed using gamma scintigraphy, and specific activity was calculated through Deferoxamine (DFO) chelation. RESULTS: 89Zr radionuclide via pressed target was effectively produced with a production yield of 20-30 MBq/µA.h, and the purification was achieved in 35 minutes with (87.46)% average recovery and >98% purity while using automated purification, but manual purification took 2 hours with (91 ± 2)% recovery and >98% purity. The production yield was comparable to the reported pressed target approach. Deferoxamine (DFO) chelation with 89Zr-oxalate was performed with purity >98% and specific activity of 25-30 µCi/mmol. CONCLUSION: In this study, we explored the production of 89Zr by pressed targets and purification via manual or automated methods with good radionuclide purity. The chelation with DFO or its analog was performed with good labeling efficiency and stability

44Sc production from enriched 47TiO2 targets with a medical cyclotron.

44Sc is a ß+-emitter which has been extensively studied for nuclear medicine applications. Its promising decay characteristics [t1/2 = 3.97 h, E [Formula: see text] = 632 keV (94.3%), Eγ = 1157 keV (99.9%); 1499 keV (0.91%)] make it highly attractive for clinical PET imaging, offering an alternative to the widely used 68Ga [t1/2 = 67.7 min, E [Formula: see text] = 836 keV (87.7%)]. Notably, its nearly fourfold longer half-life opens avenues for applications with biomolecules having extended biological half-lives and enables the centralized distribution of 44Sc radiopharmaceuticals. An additional advantage of employing 44Sc as a diagnostic radioisotope lies in its counterpart, the ß--emitter 47Sc, which is currently under investigation for targeted radiotherapy. Together, they form an ideal theranostic pair, providing a comprehensive solution for both diagnostic imaging and therapeutic applications in nuclear medicine. At the Bern medical cyclotron, a study to optimize the production of scandium radioisotopes is currently ongoing. In this context, proton irradiation of titanium targets has been investigated, exploiting the reactions 47Ti(p,α)44Sc and 50Ti(p,α)47Sc. This approach enables the production of Sc radioisotopes within a single PET medical cyclotron facility, employing identical chemical procedures for target preparation and post-irradiation processing. In this paper, we report on cross-section measurements of the 47Ti(p,α)44Sc nuclear reaction using 95.7% enriched 47TiO2 targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Production tests were performed to confirm these findings.

Density reduction effects on the production of [11C]CO2 in Nb-body targets on a medical cyclotron.

Medical isotope production of 11C is commonly performed in gaseous targets. The power deposition of the proton beam during the irradiation decreases the target density due to thermodynamic mixing and can cause an increase of penetration depth and divergence of the proton beam. In order to investigate the difference how the target-body length influences the operation conditions and the production yield, a 12 cm and a 22 cm Nb-target body containing N2/O2 gas were irradiated using a 13 MeV proton cyclotron. It was found that the density reduction has a large influence on the pressure rise during irradiation and the achievable radioactive yield. The saturation activity of [11C]CO2 for the long target (0.083 Ci/µA) is about 10% higher than in the short target geometry (0.075 Ci/µA).

Experimental assessment of nuclear cross sections for the production of Tb radioisotopes with a medical cyclotron.

155Tb is one of the most interesting radionuclides for theranostic applications. It is suitable for SPECT imaging and it can be used as a true diagnostic partner of the therapeutic 149Tb and 161Tb. Its production by proton irradiation using enriched 155Gd and 156Gd oxide targets is currently being investigated and represents a promising solution. To achieve the level of radionuclidic purity required in the clinical setting, the co-production of Tb impurities has to be minimized. For this purpose, an accurate knowledge of the cross sections of the nuclear reactions involved is of paramount importance. In this paper, we report on the assessment of cross sections of the reactions 154Gd(p,xn)153,154,154m1,154m2Tb, 155Gd(p,xn)154,154m1,154m2,155Tb, 156Gd(p,xn)155,156Tb and 157Gd(p,2n)156Tb derived with a specific data analysis procedure developed by our group. This method allows to disentangle the nuclear contributions from the production cross section by inverting linear systems of equations and it requires the measurement of the cross sections from as many materials as the reactions involved in the production of the radionuclide under study. For this purpose, the experimental data previously measured by our group at the Bern medical cyclotron by irradiating natural Gd2O3, enriched 155Gd2O3 and enriched 156Gd2O3 targets were used. For some of these nuclear reactions, cross sections were assessed for the first time. On the basis of our findings, production yield and purity can be calculated for any kind of isotopic composition of the enriched material.

Cross-section measurement of thulium radioisotopes with an 18 MeV medical PET cyclotron for an optimized 165Er production.

165Er is a pure Auger-electron emitter with promising characteristics for therapeutic applications in nuclear medicine. The short penetration path and high Linear Energy Transfer (LET) of the emitted Auger electrons make 165Er particularly suitable for treating small tumor metastases. Several production methods based on the irradiation with charged particles of Er and Ho targets can be found in the literature. In this paper, we report on the study of 165Er indirect production performed via the 166Er(p,2n)165Tm →165Er reaction at the 18 MeV Bern medical cyclotron. Despite the use of highly enriched 166Er2O3 targets, several Tm radioisotopes are produced during the irradiation, making the knowledge of the cross sections involved crucial. For this reason, a precise investigation of the cross sections of the relevant nuclear reactions in the energy range of interest was performed by irradiating Er2O3 targets with different isotopic enrichment levels and using a method based on the inversion of a linear system of equations. For the reactions 164Er(p, γ)165Tm, 166Er(p,n)166Tm, 166Er(p, γ)167Tm, 167Er(p,3n)165Tm, 167Er(p, γ)168Tm, 168Er(p,2n)167Tm and 170Er(p,3n)168Tm, the nuclear cross section was measured for the first time. From the results obtained, the production yield and purity of the parent radioisotope 165Tm were calculated to assess the optimal irradiation conditions. Several production tests with solid targets were performed to confirm these findings.

Optimized production of 67Cu based on cross section measurements of 67Cu and 64Cu using an 18 MeV medical cyclotron.

RadioNuclide Therapy (RNT) in nuclear medicine is a cancer treatment based on the administration of radioactive substances that specifically target cancer cells in the patient. These radiopharmaceuticals consist of tumor-targeting vectors labeled with ß-, α, or Auger electron-emitting radionuclides. In this framework, 67Cu is receiving increasing interest as it provides ß--particles accompanied by low-energy γ radiation. The latter allows to perform Single Photon Emission Tomography (SPECT) imaging for detecting the radiotracer distribution for an optimized treatment plan and follow-up. Furthermore, 67Cu could be used as therapeutic partner of the ß+-emitters 61Cu and 64Cu, both currently under study for Positron Emission Tomography (PET) imaging, paving the way to the concept of theranostics. The major barrier to a wider use of 67Cu-based radiopharmaceutical is its lack of availability in quantities and qualities suitable for clinical applications. A possible but challenging solution is the proton irradiation of enriched 70Zn targets, using medical cyclotrons equipped with a solid target station. This route was investigated at the Bern medical cyclotron, where an 18 MeV cyclotron is in operation together with a solid target station and a 6-m-long beam transfer line. The cross section of the involved nuclear reactions were accurately measured to optimize the production yield and the radionuclidic purity. Several production tests were performed to confirm the obtained results.

Production of Co-58m in a siphon-style liquid target on a medical cyclotron.

We present the production of 58mCo on a small, 13 MeV medical cyclotron utilizing a siphon style liquid target system. Different concentrated iron(III)-nitrate solutions of natural isotopic distribution were irradiated at varying initial pressures and subsequently separated by solid phase extraction chromatography. The radio cobalt (58m/gCo and 56Co) was successfully produced with saturation activities of (0.35 ± 0.03) MBq µA-1 for 58mCo with a separation recovery of (75 ± 2) % of cobalt after one separation step utilizing LN-resin.

Alternative routes for 64Cu production using an 18 MeV medical cyclotron in view of theranostic applications.

Radiometals play a fundamental role in the development of personalized nuclear medicine. In particular, copper radioisotopes are attracting increasing interest since they offer a varying range of decay modes and half-lives and can be used for imaging (60Cu, 61Cu, 62Cu and 64Cu) and targeted radionuclide therapy (64Cu and 67Cu), providing two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Currently, the most widely used in clinical applications is 64Cu, which has a unique decay scheme featuring ß+-, ß--decay and electron capture. These characteristics allow its exploitation in both diagnostic and therapeutic fields. However, although 64Cu has extensively been investigated in academic research and preclinical settings, it is still scarcely used in routine clinical practice due to its insufficient availability at an affordable price. In fact, the most commonly used production method involves proton irradiation of enriched 64Ni, which has a very low isotopic abundance and is therefore extremely expensive. In this paper, we report on the study of two alternative production routes, namely the 65Cu(p,pn)64Cu and 67Zn(p, α)64Cu reactions, which enable low and high 64Cu specific activities, respectively. To optimize the 64Cu production, while minimizing the mass of copper used as a target in the first case, or the co-production of other copper radioisotopes in the second case, an accurate knowledge of the production cross sections is of paramount importance. For this reason, the involved nuclear reaction cross sections were measured at the Bern medical cyclotron laboratory by irradiating enriched 65CuO and enriched 67ZnO targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Several production tests were performed to confirm these findings.

Quantification of 37Ar emanation fractions from irradiated natural rock samples and field applications.

Underground-produced 37Ar can be used for underground nuclear explosions (UNE) detection and for groundwater dating. The quantification of the emanation, that is the fraction of activity produced in the rock that escapes to the pore space, is essential for predicting the background activity expected in natural environments. We propose an experiment in which artificial CaCO3 powder and natural rock particles are irradiated with neutrons in a routinely operated medical cyclotron, whose energy spectrum is experimentally measured. The produced activity was quantified and compared with the emanated activity to determine the emanating fraction. The results showed consistent and reproducible patterns with a dominance of the recoil process at small scales (<2 mm). We observed emanation values ≤1% with a dependency on the grain size and the inner geometry of particles. Soil weathering and the presence of water increased the recoil emanation. The atoms produced that were instantaneously recoiled in the intra- or inter-granular pore space left macroscopic samples by diffusion on timescales of days to weeks (Deff = 10-12 - 10-16 m2 s-1). This diffusive transport determines the activity that prevails in the fluid-filled pore space accessible for groundwater or soil gas sampling.

47Sc and 46Sc cross-section measurement for an optimized 47Sc production with an 18 MeV medical PET cyclotron.

The availability of novel radionuclides plays a fundamental role in the development of personalized nuclear medicine. In particular, there is growing interest in pairs formed by two radioisotopes of the same element, the so-called true theranostic pairs, such as 61,64Cu/67Cu, 43,44Sc/47Sc and 155Tb/149,161Tb. In this case, the two radionuclides have identical kinetics and chemical reactivity, allowing to predict whether the patient will benefit from a therapeutic treatment on the basis of nuclear imaging data. 47Sc [t1/2 = 3.349 d, E [Formula: see text] = 440.9 keV (68.4%); 600.3 keV (31.6%), Eγ = 159.4 keV (68.3%)] is a promising radionuclide for theranostic applications in nuclear medicine. Its physical characteristics make it suitable for radionuclide therapy and allow SPECT imaging during treatment. Moreover, 47Sc is foreseen as the therapeutic partner of the ß+-emitters 43Sc and 44Sc, both under study for PET imaging, opening new avenues towards the true theranostics concept. 47Sc can be produced by proton irradiation of an enriched 50Ti oxide target with a medical cyclotron equipped with a solid target station. To optimize the production yield and the radionuclidic purity, an accurate knowledge of the production cross sections is necessary. In this paper, we report on measurements of the production cross section of 47Sc and 46Sc using enriched 50Ti titanium oxide targets, performed at the Bern University Hospital cyclotron laboratory. On the basis of the obtained results, a study of the production yield and purity was performed to assess the optimal irradiation conditions. A production test was also carried out to confirm these findings.

Cross section measurement of terbium radioisotopes for an optimized 155Tb production with an 18 MeV medical PET cyclotron.

155Tb [t1/2 = 5.32 d, Eγ = 87 keV (32%); 105 keV (25%) (IAEA, 2021)] is a novel promising radionuclide for theranostic applications in nuclear medicine. Its physical properties make it suitable for single photon emission computed tomography (SPECT) imaging, while its chemistry allows it to be used as a diagnostic partner for therapeutic radiolanthanides or pseudo-radiolanthanides, such as 177Lu and 90Y. Moreover, 155Tb could be used as a precise diagnostic match for the ß--emitter 161Tb, opening doors for the true theranostics concept. The availability of 155Tb in quantity and quality suitable for medical applications is an open issue and its production with medical cyclotrons via the 155Gd(p,n)155Tb and 156Gd(p,2n)155Tb nuclear reactions represents a possible but challenging solution. For this purpose, an accurate knowledge of the production cross sections is mandatory. In this paper, we report on the measurement of the production cross sections of 155Tb and other terbium radionuclides formed by proton irradiation of natGd2O3, 155Gd2O3 and 156Gd2O3 enriched targets, performed at the Bern University Hospital cyclotron laboratory. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. The results of several production tests are also presented.

Cross-section measurement for an optimized 61Cu production at an 18 MeV medical cyclotron from natural Zn and enriched 64Zn solid targets.

The availability of novel medical radionuclides is a key point in the development of personalised nuclear medicine. In particular, copper radioisotopes are attracting considerable interest as they can be used to label various molecules of medical interest, such as proteins and peptides, and offer two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Although 64Cu (t1/2 = 12.7006 h, ß+: 17.6%, ß-: 38.5%) is nowadays the most commonly used as a diagnostic radionuclide, 61Cu (t1/2 = 3.339 h, ß+: 61%) features more favourable nuclear properties, such as a higher positron decay fraction and the absence of ß- emissions. To date, the production of 61Cu has been carried out irradiating highly enriched 61Ni targets with a low energy proton beam. However, the use of the very expensive 61Ni targets requires an efficient recovery of the target material and makes this method quite inconvenient. Another promising production route is the proton irradiation of natural Zn or enriched 64Zn targets, exploiting the (p,α) nuclear reaction. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with an external beam transfer line and a solid target station. In this paper, we report on cross-section measurements of the 64Zn(p,α)61Cu nuclear reaction using natural Zn and enriched 64Zn material, which served as the basis to perform optimized 61Cu production tests with solid targets.

Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends.

Background: Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim: To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods: Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic "Working Group Radiochemistry and Radiopharmacy" (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results: In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion: The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects.

Assessment of radionuclide impurities in [18F]fluoromethylcholine ([18F]FMCH).

PURPOSE: [18F]Fluoromethylcholine ([18F]FMCH) is a radiopharmaceutical used in positron emission tomography (PET) imaging for the study of prostate, breast, and brain tumors. It is usually synthesized in cyclotron facilities where 18F is produced by proton irradiation of [18O]H2O through 18O(p,n)18F reaction. Due to the activation of target materials, the bombardment causes unwanted radionuclidic impurities in [18O]H2O, that need to be removed during the radiopharmaceutical synthesis. Thus, the aim of this study is to quantify the radionuclide impurities in the 18F production process and in the synthesized [18F]FMCH, demonstrating the radionuclidic purity of this radiopharmaceutical. METHODS: Long-lived radionuclide impurities were experimentally assessed using high-resolution gamma and liquid scintillation spectrometries, while short-lived impurities were monitored analyzing the decay curve of the irradiated [18O]H2O with an activity calibrator. As spectrometric radionuclide library, a Geant4 Monte Carlo simulation of the 18F-target assembly was previously performed. RESULTS: 3H, 52,54Mn, 56,57,58Co, 95m,96Tc, 109Cd, and 184Re were found in the irradiated [18O]H2O, but no radionuclide was found in the non-irradiated [18O]H2O neither in the final [18F]FMCH solution with an activity concentration greater than the minimum detectable activity concentration. A total impurity activity <6.2 kBq was measured in the irradiated [18O]H2O, whereas a [18F]FMCH radionuclide purity >99.9999998% was estimated. Finally, the decay curve of the irradiated [18O]H2O revealed a very low maximum of 13N activity (<0.03% of 18F) even immediately after the end of bombardment. CONCLUSIONS: This study demonstrated the radionuclidic purity of [18F]FMCH according to the EU Pharmacopeia.

Compelling Case for Fostering Titanium-45 for Positron Emission Tomography Tracer Applications.

The growth of diagnostic nuclear medicine is substantially based on the development, availability, and regular clinical use of cyclotron-based positron emission tomography (PET) tracers. Apart from 18F (110 min) products, the radiometal 68Ga isotope (68 min) has found an increasingly wide clinical acceptance. There is hence much merit in identifying and fostering other radiometal positron emitters, of preferably longer half-life. Titanium-45 (3.08 h) fits the bill well in this context, as it is easy to produce using natural scandium metal target and Ep of 13-14 MeV for 45Sc(p, n) 45Ti reaction. This Commentary cites a compelling case to foster the development of 45Ti products for PET imaging.

Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target.

PURPOSE: In recent years the use of 68Ga (t1/2 = 67.84 min, ß+: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of 68Ga via the 68Zn(p,n)68Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand. METHODS: Irradiations of 1.7 Msolution of 68Zn(NO3)2 in 0.2 N HNO3 were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of 67Ga through the68Zn(p,2n)67Ga reaction. The product's activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector. RESULTS: The saturation yield of68Ga amounts to (330 ±â€¯20) MBq/µA, corresponding to a produced activity of68Ga at the EOB of (4.3 ±â€¯0.3) GBq in a typical production run at 46 µA for 32 min. The radionuclidic purity of the68Ga in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80-90%. CONCLUSIONS: In summary, this approach provides clinically relevant amounts of68Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the68Ge/68Ga generators.

Pressure rise in medical cyclotron liquid targets: Transient analysis.

Transient behavior of proton-beam bombarded liquid-targets are studied at various initial conditions at the TR13 cyclotron at TRIUMF. Depending on the initial condition, experiments show a range of different responses from steady-state to self-sustained oscillations. To address this, a system of equations based on the conservation of mass and energy is proposed. Coupling between the beam and fluid-density and chemical reactions driven by the beam (radiolysis) are identified as the main reasons to describe this behavior. Excellent qualitative agreements are achieved.